Principal Investigator/Program Director (Last, first, middle): Artis, David RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3079-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 4174-artis_abstract_26june.pdf Mime Type: application/pdf 7. * Project Narrative 4958-25_narrative_26june.pdf Mime Type: application/pdf 8. Bibliography &References Cited 5451-25_literature_26june.pdf Mime Type: application/pdf 9. Facilities &Other Resources 6412-Artis_Lab_Resources.pdf Mime Type: application/pdf 10. Equipment 7962-25_equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Artis, David Soil transmitted helminths remain the most prevalent of all chronic human infections, with an estimated two billion people infected worldwide. Field and experimental studies have shown that immunity in infected individuals is associated with expression of T helper type 2 (TH2) cytokines, while persistent heavy infections can result in overproduction of proinflammatory cytokines and the development of severe intestinal inflammation. The long term goals of this proposal are to define the immunological pathways that control T helper cell differentiation and subsequent infection outcome, including intestinal inflammation. Employing experimental Trichuris infection of mice, preliminary studies identified two critical roles for IL-25 (IL-17E) in regulating the immune response following infection: first, IL-25 expression is necessary for the development of protective TH2 responses in resistant mice;second, during persistent infection, IL-25 is an important immunoregulatory cytokine that prevents the development of infection- induced intestinal inflammation. However, the cellular and molecular pathways that orchestrate the effects of IL-25 during Trichuris infection remain unknown. Using cell lineage-specific deletions in transcription factors, cytokines or cytokine receptors, three specific aims of this project will determine (i) how IL-25 promotes TH2 cytokine responses, (ii) how IL-25 limits expression of macrophage-derived proinflammatory cytokines and prevents intestinal inflammation, and (iii) how IL-25 regulates the maintenance and function of Trichuris-responsive TH2 memory cells. In addition to testing the prophylactic and therapeutic potential of IL-25 during helminth infection, the findings of these studies will have broader implications for the treatment of multiple TH2 cytokine-associated inflammatory diseases including asthma, allergy and ulcerative colitis. Project Description Page 6